Nobody knows how to engineer a virus from scratch

Interview/ Stanley Perlman, microbiologist

Professor of microbiology and immunology, as well as professor of paediatrics at the University of Iowa, Stanley Perlman has researched coronaviruses for nearly four decades and his lab has developed mouse models for studying vaccines and therapies. In this interview, he compares Covid-19 with other coronaviruses, comments on the lab leak theoryimmunity of children to Covid-19, outbreak preparedness and on the ongoing tug of war between nations for vaccines. 

What led to your interest in coronaviruses?

It happened with the discovery of human coronavirus HCoV-OC43. It is a member of the species Betacoronavirus 1, which infects humans and cattle. [Being] a paediatrician, I was interested in how viruses interact with brains. This coronavirus causes demyelination that occurs when there is a damage on the protective coating of nerve cells. It affects the spinal cord and causes neurological problems, including multiple sclerosis. I became interested in that because the host or the body seemed to be able to clear the virus without causing a lot of tissue destruction. So that's what made me interested for the 20 years that I worked before SARS came about.  

The earliest reports of coronavirus infections in animals were from North Dakota in the US in the late 1920s—in newborn chicks, with mortality rates of around 50 per cent.

I don't know if it was identified as coronavirus then, because that required electron microscopy. But IBV (Infectious Bronchitis Virus), as it was called, was the first one to be identified as coronavirus. It was a highly infectious virus that affected the respiratory tract, gut, kidney and reproductive systems of chickens.  

Even though the spread was only among animals, American scientists quickly studied it and filed a report as early as 1931. Considering that history, and the fact that deadly human infections have been around since the 1970s, do you think China had difficulty containing the Covid-19 outbreak?

You are dealing with a lot of different viruses. The human viruses that were discovered in the 1960s caused the common cold and they are everywhere in the world. Certainly SARS was present in China in 2003. So they definitely had an experience with one of these bad human coronaviruses. In December 2019, when the virus was first found in Wuhan, I think China initially did not quickly report that they had an infection and they allowed people to leave Wuhan. So they didn't contain it terribly well. But right after that, they contained it very well with the lockdown in Wuhan for many, many weeks. It would have been better if they had contained it better in the beginning.  

So, there was a chance to isolate the virus in Wuhan itself, had the scientists and the WHO taken urgent, adequate measures?  

Maybe. It really is unclear because there are now reports coming out that maybe the virus was actually in different places earlier in the fall of 2019. So, even if it was in other places in October 2019, the first case came up on December 10 and the recognition of it came 20 days after that. Certainly in retrospect, those 20 days mattered. Had they locked down the city and prevented spread, maybe it would have been right. But there is also a chance that it was in other places at the same time and so even if it would have been stopped in Wuhan it might have spread in other places. All we know for sure is that China did not move as quickly as we would have liked and there was information that they weren't sharing days to weeks after they had it.  

The spikes distinguish coronaviruses from other common viruses. But not much is known publicly about the evolutionary aspects of these spikes—what do they signify and what is their role in making the virus deadly?

One thing all viruses do is that they all attach into a cell in order to make more viruses. Because viruses have only one goal: to make more viruses. If only they can get into cells and make more viruses, they are happy. So some viruses like coronaviruses have spikes sticking out of the virus but others like the polio virus have ridges that bind to the receptor host cell. Because they don't have spikes, they are not called coronaviruses. But they can still bind to cells. So, the spike protein itself is not terribly special, except that it is the protein that is used to enter cells. If you can stop a virus from entering a cell, then you stop the infection. So, that is why mice don't get infected with SARS Coronavirus 2. So if you take a mouse and take a lot of viruses and put them in the mouse, nothing will happen. The viruses with all their spikes sticking out of them cannot find the right receptor to go into. So, it's really key to have the receptor.  

Are the spikes on Covid-19 and its genome an entirely evolutionary aspect?

Among a whole range of coronaviruses there is nothing special about the Covid-19 spike protein. What is unique about SARS-CoV-2 is that it actually grows in your noses, as against the other severe coronaviruses that grow in the lungs and then spread. Because Covid-19 grows in the nose, people who do not have symptoms or those who are about to get sick can spread the virus as well. That did not happen with SARS or MERS.  

What is your opinion on the tug-of-war between the developed and developing world regarding big pharma and vaccine profiteering?  

You in India know more about that than I do. We need as much vaccine as we can get to the world. India needs as much vaccine as it can get. Of course, the ideal situation is to have a vaccine accessible to everyone but the problem is that there just isn't enough vaccine yet.

But there is an oversupply of vaccines in your country.

Yes, that is true. And it should go to those who don't have it. But the numbers are huge. India needs as much vaccine as the whole of Western Europe and the US, as it is such a big country. There is an issue there.  

In Februry 2020, you co-signed a letter that appeared in The Lancet, saying that SARS-CoV-2 was not a bio-engineered virus and condemned conspiracy theories suggesting that Covid-19 does not have a natural origin. But now with the lab leak theory getting louder than ever, what is your take?

In another upcoming letter in The Lancet, we say the same things we said way back in February 2020. The lab leak idea has really changed. The original letter was written about [the virus] being engineered. But now a lab leak means a natural virus could have been in a lab in China and released accidentally when someone just walked out of it. That's very different from an engineered virus. I still think the lab leak is unlikely because there is no evidence for it, but it is much harder to disprove it. I can tell you that nobody can engineer a virus because nobody is that smart enough. But I can't tell you that somebody didn't get the virus while they were in a bat cave or in the lab and they happened to be there and they walked out and infected people. There is no record of it.  

You could easily get infected with Covid-19 tomorrow by somebody who you don't even know is sick. So this feels to me more like that—it could be accidental. I can say for sure that no engineering of the virus occurred. In my opinion, the way the virus came from the natural variant is found to be the most likely explanation—whether that occurred because there was an animal in the market or someplace else and humans in the middle became infected and brought the virus to Wuhan or somebody in the lab brought it, it is all a natural virus.  

You are saying nobody knows how to engineer a virus? Despite having all the knowledge, technology and resources at their disposal?

Yes. Nobody knows how to do it. I work with these viruses all the time and I wouldn't know any better. China has everything at its disposal but you still gotta learn how to do it. Consider that you have the biggest factory in the world, but if you don't know how to build a car, you can't build a car. We do not know how to make one of these viruses from scratch. All we could do is if somebody had the virus in hand, almost the whole thing, maybe they could do something to it but they wouldn't know what to do. Because viruses are pretty perfect. We mutate the virus all the time in our lab; we change the virus and they always become weaker. They never become more virulent. So, it's a good idea in theory but very, very hard to execute in practice.  

But they were carrying out gain-of-function research at the lab which means making the virus more virulent. Isn't it?          

They are not making it more virulent. They are taking a virus that they know and are putting a different spike protein on it. That's what they are doing. So the gain-of-function is that it can now infect a different cell. You have not taken a virus that never existed. You are taking a virus that is well known and are changing the spike protein—a very simple thing to do. It could be a gain of function because you could make the weak virus more virulent but it wouldn't be SARS-CoV-2; you would be taking a known virus and putting a known spike protein on it. It's not magic. You are not taking an unknown virus and an unknown spike protein and coming up with SARS-CoV-2. So, they did not make the virus from scratch.  

So, if I understand it correctly, you are saying that they already had a SARS-CoV-2 virus in the lab which they took to modify by adding a spike protein so as to mutate it further?

It would have helped to have the virus in the lab. Then the second thing they would have to have, is the spike protein they which would make it more virulent. Third thing is that if they had everything they would put it into the virus, they still wouldn't know what they were gonna get. I mean it is not like following a recipe with a virus in front of them. You really have to know it, to begin doing it.  

In terms of gender, do you observe that men are more affected than women by Covid-19?

Yes. Men seem to get sicker with it. They have higher chances to be hospitalised and suffer from the severity of the disease. Women only and mostly tend to lose their sense of smell and taste. I think it has to do with some of the female hormones that are protective. But we haven't understood it fully yet. But this is true not just for the US, but also Europe, China, etc. Everywhere we see men to be the worst affected.    

You feel that some of the ways in which the US managed the spread of infection was less than ideal? What are the lessons in management that you have learnt and what would you suggest to a developing country like ours?

In the US, cases came in from China or Europe very early, probably in 2019 itself and that point the first thing one needs is a leader who says we have a big problem. Neither the US nor India had that. Both of them said it is not a big deal. So the moment you know the virus is in, you have to start tracing people like they did in South Korea. In the US we needed to have contact tracing and hospital infrastructure in place and enough hospitals, too. Again, the same problems were seen in India, too. Both countries were bad because in the US we had a warning. We saw what was going on in China and should have been prepared. And India has had a year of warning before the second wave occurred. Even now, the average population of the US completely vaccinated is not more than 62 per cent. In my state of Iowa, there are only 25 per cent people who are vaccinated. Because even in a developed country like the US, they think that Covid-19 does not exist and that the vaccine is a myth, that it will not protect them and go into their DNA. I think you will have problems convincing people to get vaccinated in the deeper pockets of India, just like here in places where people are very hesitant.  

Recently, there have been reports from Malaysia about canine coronaviruses, jumping directly from animal (dogs) to people and causing pneumonia in children.
I think it's an interesting story because it says coronaviruses can jump. The coronaviruses that jump are not the average canine coronaviruses. So you have one canine coronavirus called Type 1, another one called Type 2, there is a feline (cat) coronavirus called type 1, a feline coronavirus called type 2, then there is a pig coronavirus called TGEV (transmissible gastroenteritis virus).  So five different viruses that all hop back and forth between cats, dogs and pigs. The virus that crossed to people was a combination of canine coronavirus Type 1, canine coronavirus TYPE 2 and feline coronavirus Type 1. It is a cross of all these. The exact virus is not found in nature but it did cross to people and cause pneumonia in eight children. Now the problem is that with only eight children infected you can't be 100 per cent sure that the virus they find is the cause of the infection. You want to find it in a lot of people. But I believe it is the canine coronavirus.  

So now, there are dangers of transmissibility of coronaviruses from bats, cats, dogs, pigs, chicks....    

Yes. We are beginning to recognise them now. Unless something really happens, we don't see it. I'm a paediatrician and we see children with pneumonia all the time but we didn't know what it was, we would just say, Oh it's a virus. Well, we now know that maybe sometimes they are coronaviruses. We can now recognise them better.

As a paediatrician, can you throw light on how vulnerable children are in this pandemic? Because recently the WHO issued guidelines stating that children under five need not be masked. At a time when we are staring at an imminent third wave, will it be prudent to keep our children unmasked?

Some children get very sick with this (Covid-19) but a vast majority of children do not get sick. That is why we are a little lenient. But we are also hoping to immunise children pretty soon. Right now, we are vaccinating children above 12 years and then we would move on to those between 5 and 12. And then very soon, we will cover children between six months and five years of age.

You said that a vast majority of children do not get sick by Covid-19. Is it because of their inbuilt immunity? Children's immunity against the virus has been a point of contention all this while.  

We don't really know. All we know is that they do not get sick. I don't think they have specific immunity. Maybe their immune systems are stronger but it is not like they already have antibodies in response to SARS-CoV-2. Some people say that they are safer because they already have immunity to coronaviruses that cause the common cold. That is a possibility too. But we know that children between the ages of five and 12 are least likely to get sick.  

There were some reports that the Pfizer vaccine administered to children between the ages of 12 and 18 negatively impacted some children and they had to be hospitalised. Is there a need for reconsidering this vaccine for children?  

No. The data that I have seen, pertaining to the protection extended to children post vaccination, is extraordinarily good. There is no reason to worry for issues like sore throat, cough and cold. People ending up in hospitals and dying are the ones who are immunocompromised and do not have good immune systems at all.

India is looking at a possibility of a third wave. How do you suggest we tackle it if it were to hit us?

Vaccinate as many people as possible and please comply with Covid appropriate behaviour. That is all.

Dr Anthony Fauci said that the Delta variant of coronavirus found in India has proven to be the greatest threat to the efforts made by the US to fight Covid-19 in its borders. The transmissibility and severity of the Delta variant are more than the original Covid-19. What are your thoughts?    

There is no doubt that this variant spreads easily. So for example, if you and I are in the same room and we are infected with the Alpha strain or the original strain, we have a certain chance of both of us getting infected. With the Delta variant, the chances are twice as much. But whether it causes more severe disease is controversial. It may be a bit more virulent. If the number of those getting sick was 1 in 100 earlier, now it would be 10 or 11 in 800.

Are lockdown measures effective? While we had a strict national lockdown, the US had none.

A lot of people here feel that we should have had lockdowns. The problem with India was that it did not know what to do with all the migrants who wanted to head to their hometowns, and that was also a reason for the spread in infection. Otherwise it might have worked in India. Lockdowns seem to work, but they come at a great economic cost. For them to be effective you have to ensure that people have enough money so that they do not starve.  

In the late 1990s we knew only two coronaviruses—HCoV229E and OC43. These manifested as common colds. Had we paid more attention back then, this present tragedy across the world could have been averted. Is that right?  

The point is that in 2003 we had SARS and we realised that it was a bat virus and that there were other coronaviruses in bats that could infect people. That's probably when we should have paid more attention. Not 1990s as that was too early.  

Viruses play havoc with our lives. Are they any good for us?

If you never had a virus infection I don't think you would be worse off. Especially these pathogenic ones. There may be other ones living in our gut that are helpful but these are not. So, if you never had the polio, flu or the common cold, you would be just fine. We know we have viruses in our gut that infect the bacteria present there. I suspect there are some animal viruses that live in our gut, but they don't cause disease.  

India is seeing an increasing number of cases of the Delta Plus variant—at present what we know is that Delta Plus is a sub-lineage of the Delta variant first detected in India, which has acquired the spike protein mutation called K417N. Some say it is highly transmissible, while others say it is  highly infectious. Please throw light as per your experience and observations.  

I do not know the epidemiology well enough to comment. The 417 mutation is not well understood at the molecular level.  

How did the UK deal with the Delta variant? What should we know about this mutation?  

That it is more transmissible. The UK slowed down opening up and kept some social distancing rules. The country also tried to ramp up vaccination.